Targeted immunotherapy for glioblastoma involving whole tumor-derived autologous cells in the upfront setting after craniotomy.

PURPOSE: To date, immunotherapeutic approaches in glioblastoma (GBM) have had limited clinical efficacy as compared to other solid tumors. Here we explore autologous cell treatments that have the potential to circumvent treatment resistance to immunotherapy for GBM. METHODS: We performed literature review and assessed clinical outcomes in phase 1 safety trials as well as phase 2 and 3 autologously-derived vaccines for the treatment of newly-diagnosed GBM. In one recent review of over 3,000 neuro-oncology phase 2 and phase 3 clinical trials, most trials were nonblinded (92%), single group (65%), nonrandomized (51%) and almost half were GBM trials. Only 10% involved a biologic and only 2.2% involved a double-blind randomized trial design. RESULTS: With this comparative literature review we conclude that our autologous cell product is uniquely antigen-inclusive and antigen-agnostic with a promising safety profile as well as unexpected clinical efficacy in our published phase 1b trial. We have since designed a rigorous double-blinded add-on placebo-controlled trial involving our implantable biologic drug device. We conclude that IGV-001 provides a novel immunotherapy platform for historically intransigent ndGBM in this ongoing phase 2b trial (NCT04485949).

Predictors of recurrence after surgical resection of parafalcine and parasagittal meningiomas.

PURPOSE: Owing to their vicinity near the superior sagittal sinus, parasagittal and parafalcine meningiomas are challenging tumors to surgically resect. In this study, we investigate key factors that portend increased risk of recurrence after surgery. METHODS: This is a retrospective study of patients who underwent resection of parasagittal and parafalcine meningiomas at our institution between 2012 and 2018. Relevant clinical, radiographic, and histopathological variables were selected for analysis as predictors of tumor recurrence. RESULTS: A total of 110 consecutive subjects (mean age: 59.4 ± 15.2 years, 67.3% female) with 74 parasagittal and 36 parafalcine meningiomas (92 WHO grade 1, 18 WHO grade 2/3), are included in the study. A total of 37 patients (33.6%) exhibited recurrence with median follow-up of 42 months (IQR: 10-71). In the overall cohort, parasagittal meningiomas exhibited shorter progression-free survival compared to parafalcine meningiomas (Kaplan-Meier log-rank p = 0.045). On univariate analysis, predictors of recurrence include WHO grade 2/3 vs. grade 1 tumors (p < 0.001), higher Ki-67 indices (p < 0.001), partial (p = 0.04) or complete sinus invasion (p < 0.001), and subtotal resection (p < 0.001). Multivariable Cox regression analysis revealed high-grade meningiomas (HR: 3.62, 95% CI: 1.60-8.22; p = 0.002), complete sinus invasion (HR: 3.00, 95% CI: 1.16-7.79; p = 0.024), and subtotal resection (HR: 3.10, 95% CI: 1.38-6.96; p = 0.006) as independent factors that portend shorter time to recurrence. CONCLUSION: This study identifies several pertinent factors that confer increased risk of recurrence after resection of parasagittal and parafalcine meningiomas, which can be used to devise appropriate surgical strategy to achieve improved patient outcomes.

Radiomic signatures of meningiomas using the Ki-67 proliferation index as a prognostic marker of clinical outcomes.

OBJECTIVE: The clinical behavior of meningiomas is not entirely captured by its designated WHO grade, therefore other factors must be elucidated that portend increased tumor aggressiveness and associated risk of recurrence. In this study, the authors identify multiparametric MRI radiomic signatures of meningiomas using Ki-67 as a prognostic marker of clinical outcomes independent of WHO grade. METHODS: A retrospective analysis was conducted of all resected meningiomas between 2012 and 2018. Preoperative MR images were used for high-throughput radiomic feature extraction and subsequently used to develop a machine learning algorithm to stratify meningiomas based on Ki-67 indices < 5% and ≥ 5%, independent of WHO grade. Progression-free survival (PFS) was assessed based on machine learning prediction of Ki-67 strata and compared with outcomes based on histopathological Ki-67. RESULTS: Three hundred forty-three meningiomas were included: 291 with WHO grade I, 43 with grade II, and 9 with grade III. The overall rate of recurrence was 19.8% (15.1% in grade I, 44.2% in grade II, and 77.8% in grade III) over a median follow-up of 28.5 months. Grade II and III tumors had higher Ki-67 indices than grade I tumors, albeit tumor and peritumoral edema volumes had considerable variation independent of meningioma WHO grade. Forty-six high-performing radiomic features (1 morphological, 7 intensity-based, and 38 textural) were identified and used to build a support vector machine model to stratify tumors based on a Ki-67 cutoff of 5%, with resultant areas under the curve of 0.83 (95% CI 0.78-0.89) and 0.84 (95% CI 0.75-0.94) achieved for the discovery (n = 257) and validation (n = 86) data sets, respectively. Comparison of histopathological Ki-67 versus machine learning-predicted Ki-67 showed excellent performance (overall accuracy > 80%), with classification of grade I meningiomas exhibiting the greatest accuracy. Prediction of Ki-67 by machine learning classifier revealed shorter PFS for meningiomas with Ki-67 indices ≥ 5% compared with tumors with Ki-67 < 5% (p < 0.0001, log-rank test), which corroborates divergent patient outcomes observed using histopathological Ki-67. CONCLUSIONS: The Ki-67 proliferation index may serve as a surrogate marker of increased meningioma aggressiveness independent of WHO grade. Machine learning using radiomic feature analysis may be used for the preoperative prediction of meningioma Ki-67, which provides enhanced analytical insights to help improve diagnostic classification and guide patient-specific treatment strategies.

Glioblastoma with deep supratentorial extension is associated with a worse overall survival.

Glioblastoma (GBM) with deep-supratentorial extension (DSE) involving the thalamus, basal ganglia and corpus collosum, poses significant challenges for clinical management. In this study, we present our outcomes in patients who underwent resection of supratentorial GBM with associated involvement of deep brain structures. We conducted a retrospective review of patients who underwent resection of GBM at our institution between 2012 and 2018. A total of 419 patients were included whose pre-operative MRI scans were reviewed. Of these, 143 (34.1%) had GBM with DSE. There were similar rates of IDH-1 mutation (9% versus 7.6%, p = 0.940) and MGMT methylation status (35.7% versus 45.2%, p = 0.397) between the two cohorts. GBM patients without evidence of DSE had higher rates of radiographic gross total resection (GTR) compared to those with DSE: 70.6% versus 53.1%, respectively (p = 0.002). The presence of DSE was not associated with decreased progression-free survival (PFS) compared to patients without DSE (mean 7.24 ± 0.97 versus 8.89 ± 0.76 months, respectively; p = 0.276), but did portend a worse overall survival (OS) (mean 10.55 ± 1.04 versus 15.02 ± 1.05 months, respectively; p = 0.003). There was no difference in PFS or OS amongst DSE and non-DSE patients who underwent GTR, but patients who harbored DSE and underwent subtotal resection had worse OS (mean 8.26 ± 1.93 versus 12.96 ± 1.59 months, p = 0.03). Our study shows that GBM patients with DSE have lower OS compared to those without DSE. This survival difference appears to be primarily related to the limited surgical extent of resection owing to the neurological deficits that may be incurred with involvement of eloquent deep brain structures.

Cervical spinal cord injury-induced neuropathic pain in male mice is associated with a persistent pro-inflammatory macrophage/microglial response in the superficial dorsal horn.

A significant portion of individuals living with traumatic spinal cord injury (SCI) experiences some degree of debilitating neuropathic pain (NP). This pain remains largely intractable in a majority of cases, due in part to an incomplete understanding of its underlying mechanisms. Central sensitization, an increase in excitability of pain transmission neurons located in superficial dorsal horn (sDH), plays a key role in development and maintenance of SCI-induced NP. Resident microglia and peripheral monocyte-derived macrophages (referred to collectively as MMΦ) are involved in promoting SCI-induced DH neuron hyperexcitability. Importantly, these MMΦ consist of populations of cells that can exert pro-inflammatory or anti-inflammatory signaling within injured spinal cord. It is critical to spatiotemporally characterize this heterogeneity to understand MMΦ contribution to NP after SCI. Given that a majority of SCI cases are cervical in nature, we used a model of unilateral C5/C6 contusion that results in persistent at-level thermal hyperalgesia and mechanical allodynia, two forms of NP-related behavior, in the forepaw. The aim of this study was to characterize the sDH MMΦ response within intact cervical spinal cord segments caudal to the lesion (i.e. the location of primary afferent nociceptive input from the forepaw plantar surface). Cervical SCI promoted a persistent MMΦ response in sDH that coincided with the chronic NP phenotype. Using markers of pro- and anti-inflammatory MMΦ, we found that the MMΦ population within sDH exhibited significant heterogeneity that evolved over time post-injury, including a robust and persistent increase in pro-inflammatory MMΦ that was especially pronounced at later times. C5/C6 contusion SCI also induced below-level thermal hyperalgesia and mechanical allodynia in the hindpaw; however, we did not observe a pronounced MMΦ response in sDH of L4/L5 spinal cord, suggesting that different inflammatory cell mechanisms occurring in sDH may be involved in at-level versus below-level NP following SCI. In conclusion, our findings reveal significant MMΦ heterogeneity both within and across pain transmission locations after SCI. These data also show a prominent and persistent pro-inflammatory MMΦ response, suggesting a possible role in DH neuron hyperexcitability and NP.

Predictors of 30-day hospital readmission after mechanical thrombectomy for acute ischemic stroke.

OBJECTIVE: The 30-day readmission rate is of increasing interest to hospital administrators and physicians, as it is used to evaluate hospital performance and is associated with increased healthcare expenditures. The estimated yearly cost to Medicare of readmissions is $17.4 billion. The Centers for Medicare and Medicaid Services therefore track unplanned 30-day readmissions and institute penalties against hospitals whose readmission rates exceed disease-specific national standards. One of the most important conditions with potential for improvement in cost-effective care is ischemic stroke, which affects 795,000 people in the United States and is a leading cause of death and disability. Recent widespread adoption of mechanical thrombectomy has revolutionized stroke care, requiring reassessment of readmission causes and costs in this population. METHODS: The authors retrospectively analyzed a prospectively maintained database of stroke patients and identified 561 patients who underwent mechanical thrombectomy between 2010 and 2019 at the authors' institution. Univariate and multivariate analyses were conducted to identify clinical variables and comorbidities related to 30-day readmissions in this patient population. RESULTS: Of the 561 patients, 85.6% (n = 480) survived their admission and were discharged from the hospital to home or rehabilitation, and 8.8% (n = 42/480) were readmitted within 30 days. The median time to readmission was 10.5 days (IQR 6.0-14.3). The most common reasons for readmission were infection (33.3%) and acute cardiac or cerebrovascular events (19% and 20%, respectively). Multivariate analysis showed that hypertension (p = 0.030; OR 2.72) and length of initial hospital stay (p = 0.040; OR 1.032) were significantly correlated with readmission within 30 days, while hemorrhagic conversion (grades 3 and 4) approached significance (p = 0.053; OR 2.23). Other factors, such as unfavorable outcome at discharge, history of coronary artery disease, and discharge destination, did not predict readmission. CONCLUSIONS: The study data demonstrate that hypertension, length of hospital stay, and hemorrhagic conversion were predictors of 30-day hospital readmission in stroke patients after mechanical thrombectomy. Infection was the most common cause of 30-day readmission, followed by cardiac and cerebrovascular diagnoses. These results therefore may serve to identify patients within the stroke population who require increased surveillance following discharge to reduce complications and unplanned readmissions.

Revascularization and functional outcomes after mechanical thrombectomy: an update to key metrics.

OBJECTIVE: The advent of mechanical thrombectomy (MT) has become an effective option for the treatment of acute ischemic stroke in addition to tissue plasminogen activator (tPA). With recent advances in device technology, MT has significantly altered the hospital course and functional outcomes of stroke patients. The authors' goal was to establish the most up-to-date reperfusion and functional outcomes with the evolution of MT technology. METHODS: The authors conducted a retrospective study of 403 patients who underwent MT for ischemic stroke at their institution from 2010 to 2017. They collected data on patient comorbidities, National Institutes of Health Stroke Scale (NIHSS) score on arrival, tPA administration, revascularization outcomes, and functional outcomes on discharge. RESULTS: In 403 patients, the mean NIHSS score on presentation was 15.8 ± 6.6, with 195 (48.0%) of patients receiving tPA prior to MT. Successful reperfusion (thrombolysis in cerebral infarction score 2B or 3) was achieved in 84.4%. Hemorrhagic conversion with significant mass effect was noted in 9.9% of patients. The median lengths of ICU and hospital stay were 3.0 and 7.0 days, respectively. Functional independence (modified Rankin Scale score 0-2) was noted in 125 (31.0%) patients, while inpatient mortality occurred in 43 (10.7%) patients. CONCLUSIONS: As MT has established acute ischemic stroke as a neurosurgical disease, there is a pressing need to understand the hospital course, hospital- and procedure-related complications, and outcomes for this new patient population. The authors provide a detailed account of key metrics for MT with the latest device technology and identify the predictors of unfavorable outcomes and inpatient mortality.

Revascularization and functional outcomes after mechanical thrombectomy for acute ischemic stroke in elderly patients.

OBJECTIVE: Mechanical thrombectomy (MT) is now the standard of care for acute ischemic stroke (AIS) secondary to large-vessel occlusion, but there remains a question of whether elderly patients benefit from this procedure to the same degree as the younger populations enrolled in the seminal trials on MT. The authors compared outcomes after MT of patients 80-89 and ≥ 90 years old with AIS to those of younger patients. METHODS: The authors retrospectively analyzed records of patients undergoing MT at their institution to examine stroke severity, comorbid conditions, medical management, recanalization results, and clinical outcomes. Univariate and multivariate logistic regression analysis were used to compare patients < 80 years, 80-89 years, and ≥ 90 years old. RESULTS: All groups had similar rates of comorbid disease and tissue plasminogen activator (tPA) administration, and stroke severity did not differ significantly between groups. Elderly patients had equivalent recanalization outcomes, with similar rates of readmission, 30-day mortality, and hospital-associated complications. These patients were more likely to have poor clinical outcome on discharge, as defined by a modified Rankin Scale (mRS) score of 3-6, but this difference was not significant when controlled for stroke severity, tPA administration, and recanalization results. CONCLUSIONS: Octogenarians, nonagenarians, and centenarians with AIS have similar rates of mortality, hospital readmission, and hospital-associated complications as younger patients after MT. Elderly patients also have the capacity to achieve good functional outcome after MT, but this potential is moderated by stroke severity and success of treatment.

Differential Response in Novel Stem Cell Niches of the Brain after Cervical Spinal Cord Injury and Traumatic Brain Injury.

Populations of neural stem cells (NSCs) reside in a number of defined niches in the adult central nervous system (CNS) where they continually give rise to mature cell types throughout life, including newly born neurons. In addition to the prototypical niches of the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus, novel stem cell niches that are also neurogenic have recently been identified in multiple midline structures, including circumventricular organs (CVOs) of the brain. These resident NSCs serve as a homeostatic source of new neurons and glial cells under intact physiological conditions. Importantly, they may also have the potential for reparative processes in pathological states such as traumatic spinal cord injury (SCI) and traumatic brain injury (TBI). As the response in these novel CVO stem cell niches has been characterized after stroke but not following SCI or TBI, we quantitatively assessed cell proliferation and the neuronal and glial lineage fate of resident NSCs in three CVO nuclei-area postrema (AP), median eminence (ME), and subfornical organ (SFO) -in rat models of cervical contusion-type SCI and controlled cortical impact (CCI)-induced TBI. Using bromodeoxyuridine (BrdU) labeling of proliferating cells, we find that TBI significantly enhanced proliferation in AP, ME, and SFO, whereas cervical SCI had no effects at early or chronic time-points post-injury. In addition, SCI did not alter NSC differentiation profile into doublecortin-positive neuroblasts, GFAP-expressing astrocytes, or Olig2-labeled cells of the oligodendrocyte lineage within AP, ME, or SFO at both time-points. In contrast, CCI induced a pronounced increase in Sox2- and doublecortin-labeled cells in the AP and Iba1-labeled microglia in the SFO. Lastly, plasma derived from CCI animals significantly increased NSC expansion in an in vitro neurosphere assay, whereas plasma from SCI animals did not exert such an effect, suggesting that signaling factors present in blood may be relevant to stimulating CVO niches after CNS injury and may explain the differential in vivo effects of SCI and TBI on the novel stem cell niches.

Risk of Hospitalization Due to Medication Nonadherence Identified Through EMRs of Patients With Psychosis.

OBJECTIVE: This study examined whether outpatients with a psychotic disorder who are at risk of hospitalization can be identified by using data from electronic medical records (EMRs). METHODS: Data from EMRs of outpatients enrolled in two clinics for treatment of psychotic disorders were abstracted. Monthly data were collected for 75 patients over two years. The study examined the association of medication nonadherence, substance use, participation in psychiatric rehabilitation, and long-acting injectable antipsychotic use in any given month with the risk of hospitalization in the subsequent month by using generalized estimating equations. RESULTS: The only variable found to increase the relative risk of future hospitalization was recorded medication nonadherence (adjusted relative risk=7.19, p<.001). CONCLUSIONS: Results suggest that recording medication nonadherence in EMRs is feasible and that these data may be used to identify patients at high risk of future hospitalization, who may require more intensive intervention.

Analysis of differential gene expression mediated by clozapine in human postmortem brains.

Clozapine is the only medication indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents, but its mechanism of action is poorly understood. To date, no studies of human postmortem brain have characterized the gene expression response to clozapine. Therefore, we addressed this question by analyzing expression data extracted from published microarray studies involving brains of patients on antipsychotic therapy. We first performed a systematic review and identified four microarray studies of postmortem brains from antipsychotic-treated patients, then extracted the expression data. We then performed generalized linear model analysis on each study separately, and identified the genes differentially expressed in response to clozapine compared to other atypical antipsychotic medications, as well as their associated canonical pathways. We also found a number of genes common to all four studies that we analyzed: GCLM, ZNF652, and GYPC. In addition, pathway analysis highlighted the following processes in all four studies: clathrin-mediated endocytosis, SAPK/JNK signaling, 3-phosphoinositide synthesis, and paxillin signaling. Our analysis yielded the first comprehensive compendium of genes and pathways differentially expressed upon clozapine treatment in the human brain, which may provide insight into the mechanism and unique efficacy of clozapine, as well as the pathophysiology of schizophrenia.

Specialist and primary care physicians' views on barriers to adequate preparation of patients for renal replacement therapy: a qualitative study.

BACKGROUND: Early preparation for renal replacement therapy (RRT) is recommended for patients with advanced chronic kidney disease (CKD), yet many patients initiate RRT urgently and/or are inadequately prepared. METHODS: We conducted audio-recorded, qualitative, directed telephone interviews of nephrology health care providers (n = 10, nephrologists, physician assistants, and nurses) and primary care physicians (PCPs, n = 4) to identify modifiable challenges to optimal RRT preparation to inform future interventions. We recruited providers from public safety-net hospital-based and community-based nephrology and primary care practices. We asked providers open-ended questions to assess their perceived challenges and their views on the role of PCPs and nephrologist-PCP collaboration in patients' RRT preparation. Two independent and trained abstractors coded transcribed audio-recorded interviews and identified major themes. RESULTS: Nephrology providers identified several factors contributing to patients' suboptimal RRT preparation, including health system resources (e.g., limited time for preparation, referral process delays, and poorly integrated nephrology and primary care), provider skills (e.g., their difficulty explaining CKD to patients), and patient attitudes and cultural differences (e.g., their poor understanding and acceptance of their CKD and its treatment options, their low perceived urgency for RRT preparation; their negative perceptions about RRT, lack of trust, or language differences). PCPs desired more involvement in preparation to ensure RRT transitions could be as "smooth as possible", including providing patients with emotional support, helping patients weigh RRT options, and affirming nephrologist recommendations. Both nephrology providers and PCPs desired improved collaboration, including better information exchange and delineation of roles during the RRT preparation process. CONCLUSIONS: Nephrology and primary care providers identified health system resources, provider skills, and patient attitudes and cultural differences as challenges to patients' optimal RRT preparation. Interventions to improve these factors may improve patients' preparation and initiation of optimal RRTs.